Mod. Pathol. [JOURNAL]
Sun
200 papers
Expression of Programmed Death-Ligand 1 and Programmed Cell Death-1 Across the Anal Neoplasia Disease Continuum and Association With Survival in Anal Cancer.
Chowdhury S, Gasper C, Lazar AA … +4 more , Allaire K, Darragh TM, Fong L, Palefsky JM
Mod Pathol · 2026 Jan · PMID 41106476 · Publisher ↗
High-risk human papillomavirus (HPV) is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of programmed death-ligand 1 (PD-L1)- expression...
High-risk human papillomavirus (HPV) is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of programmed death-ligand 1 (PD-L1)- expression in aSCC and its impact on overall survival is controversial. ASCC can evade immune surveillance by coopting the PD-L1/programmed cell death-1 (PD-1) immune checkpoint pathway, enhancing tumorigenesis. To assess the potential role of the PD-L1/PD-1 axis on tumor progression, we assessed PD-L1 and PD-1 expression on epithelial cells and immune cells by immunohistochemistry in nonlesional anal tissue (n = 22), aHSIL (n = 22), and aSCC (n = 52) from HIV-negative participants and people living with HIV. PD-L1 expression on epithelial cells was restricted to tumor cells with no expression in nonlesional and HSIL tissues, whereas PD-L1-positive immune cells were present across all 3 diagnostic stages. PD-1 expression was absent on epithelial cells, whereas PD-1-positive immune cells increased along the disease continuum from nonlesional to aSCC. The overall PD-L1 expression on epithelial cells and immune cells measured by the combined positive score (CPS) in aSCC and the aggregate PD-L1 score in nonlesional and HSIL showed a substantial increase from nonlesional to aHSIL to aSCC. In aSCC, PD-L1 expression on immune cells was more prominent than in tumor cells and correlated with increased immune cell infiltration and interferon gamma secretion. Ninety-two percent of aSCC exhibited an adaptive PD-L1 expression pattern characterized by PD-L1 expression on tumor cells, immune cells, or both. HIV status did not affect PD-L1/PD-1 expression in nonlesional, aHSIL, or aSCC. PD-L1 expression in treatment-naive aSCC was associated with improved overall survival. Those with CPS of 0 had a higher risk of death (hazard ratio, 15.2 [95% CI, 3.3-69; P = .0004; log-rank P < .0001]) compared with those with CPS >0. CPS may indicate the presence of immune activation and serve as a potential prognostic marker.
Cribriform Tumor of the Skin: Identification of 6q and 9q Loss as a Recurrent Cytogenomic Alteration.
Ronen S, Grand DG, Khan WA … +5 more , Michal M, Green DC, Ko JS, LeBlanc RE, Cloutier JM
Mod Pathol · 2026 Jan · PMID 41101595 · Full text
Cribriform tumor is a rare sweat-gland neoplasm of uncertain malignant potential. Although its histopathologic features are well described, the molecular underpinnings of cribriform tumor remain incompletely characterize...
Cribriform tumor is a rare sweat-gland neoplasm of uncertain malignant potential. Although its histopathologic features are well described, the molecular underpinnings of cribriform tumor remain incompletely characterized. We performed comprehensive molecular profiling of 6 cribriform tumors from 3 institutions using whole-exome sequencing, transcriptome sequencing, and single-nucletide polymorphism array copy number analysis. The cohort included 3 women and 3 men (median age, 54 years; range, 40-66 years), with tumors measuring 0.3 to 2.0 cm. Most arose on the extremities, with one located on the back. The most consistent genomic alteration was arm-level losses of chromosomes 6q and 9q, detected in 5 out of 6 cases. These alterations were validated across independent sequencing and single-nucletide polymorphism array platforms. Whole-exome sequencing identified likely pathogenic variants in 2 tumors (CHEK2 p.R145W and NF1 p.R1830H). No gene fusions were detected. Taken together, these findings provide independent confirmation that 6q/9q loss represents a consistent cytogenomic alteration in cribriform tumor, supporting its use as a molecular hallmark of this tumor.
Methylation Profiles in Bone and Soft Tissue Tumors: Do They Help Classify the Unclassifiable?
Dermawan JK
Mod Pathol · 2025 Dec · PMID 41093146 · Publisher ↗
Methylation profiling offers a promising avenue for improving the diagnosis and classification of bone and soft tissue tumors, particularly in cases where traditional methods fall short. Through examining tissue- and lin...
Methylation profiling offers a promising avenue for improving the diagnosis and classification of bone and soft tissue tumors, particularly in cases where traditional methods fall short. Through examining tissue- and lineage-specific DNA methylation patterns, this approach can augment the classification of morphologically similar tumors with different genetics (genetic heterogeneity) or tumors that share genetic drivers but diverge phenotypically (phenotypic heterogeneity). This tool can also help clarify previously unclassifiable, poorly differentiated or transdifferentiated nonmesenchymal tumors that mimic sarcomas. By adopting an unbiased approach to grouping and subtyping using unsupervised clustering on methylomes, methylation profiling could potentially revise how we classify sarcomas. There is a need clinically to develop a methylation classifier that accurately predicts sarcoma class based on methylation profile, specifically in sarcomas that are challenging to differentiate due to overlapping morphologic or molecular features. However, current classifiers are limited by the diversity and size of their reference cohorts, dilution of signal by nonneoplastic tissue, and alteration of the methylomic landscape by histone modifications and oncometabolite-related mutations. Key considerations include the importance of quality control for tissue-based methylation profiling, transparent and reproducible pipelines, and open data sharing. Future advancements include continued refinement of methylation-based classifiers with a broader spectrum of rare and ultrarare tumor types and adopting new biological insights from methylome-driven analyses and integration of multiomic approaches. Although methylation profiling emerges as a valuable adjunct to existing diagnostic modalities, clinicopathologic considerations should always be incorporated for a more nuanced, management-based tumor classification system.
Tumors of the Synovium.
Tang YL, Husseini J, Nielsen GP
Mod Pathol · 2026 Jan · PMID 41093145 · Publisher ↗
The synovium is an integral component of synovial joints, as well as extra-articular structures such as the tenosynovium and bursae. This article reviews normal histology and the immunohistochemical profile of the synovi...
The synovium is an integral component of synovial joints, as well as extra-articular structures such as the tenosynovium and bursae. This article reviews normal histology and the immunohistochemical profile of the synovium. It also discusses several common and distinctive intra-articular and extra-articular tumors arising in synovium-lined structures, such as tenosynovial giant cell tumor, synovial chondromatosis, and the recently described chondroid synoviocytic neoplasm. Among these, tenosynovial giant cell tumor and chondroid synoviocytic neoplasm are the only true neoplasms of synoviocytes. An emerging entity, calcified chondroid mesenchymal neoplasm, will also be mentioned. The clinical, radiologic, morphologic, and molecular genetics features of these tumors are discussed, along with their differential diagnoses. In addition, the article addresses other rare lesions, such as lipoma arborescens, a nonneoplastic condition, and synovial hemangioma, which often present as an intra-articular mass. Finally, a brief overview of selected primary intra-articular sarcomas is provided.
Unraveling Round Cell Sarcomas: A Contemporary Diagnostic Guide Beyond Ewing Sarcoma.
Perret RE
Mod Pathol · 2026 Jan · PMID 41093144 · Publisher ↗
Round cell sarcomas represent a continuously evolving category of malignant mesenchymal tumors, currently encompassing 5 main tumor subtypes: Ewing sarcoma, Capicua Transcriptional Repressor (CIC)-rearranged sarcoma, sar...
Round cell sarcomas represent a continuously evolving category of malignant mesenchymal tumors, currently encompassing 5 main tumor subtypes: Ewing sarcoma, Capicua Transcriptional Repressor (CIC)-rearranged sarcoma, sarcomas with BCL6-corepressor (BCOR)-genetic abnormalities, POZ/BTB and AT hook containing zinc finger 1 (PATZ1)-rearranged sarcoma, and nuclear factor of activated T cells 2 (NFATC2)-rearranged sarcoma. These tumors show some degree of histomorphologic overlap, which, coupled with their infrequency, may render their diagnosis challenging for the pathologist. Furthermore, although ancillary techniques like immunohistochemistry and molecular tests can be of diagnostic aid, they are still limited by inherent sensitivity and specificity issues and cannot replace meticulous integration of clinical and radiologic findings. This review is focused on (1) providing a guide for tackling the diagnosis of round cell sarcomas and their mimics using an integrative approach combining demographics, clinicoradiologic data, histomorphology, and ancillary techniques and (2) detailing the most recent information on round cell sarcomas from the latest World Health Organization classification of Bone and Soft Tissue Tumors (fifth edition).
Non-neoplastic Orthopedic Pathology Updates: Common Problems and Pitfalls and How to Avoid Them.
Kilpatrick SE
Mod Pathol · 2025 Dec · PMID 41093143 · Publisher ↗
Despite representing <1% of all musculoskeletal surgical pathology cases, primary musculoskeletal neoplasms are disproportionately emphasized in the surgical pathology literature, compared with non-neoplastic orthopedic...
Despite representing <1% of all musculoskeletal surgical pathology cases, primary musculoskeletal neoplasms are disproportionately emphasized in the surgical pathology literature, compared with non-neoplastic orthopedic pathology. Yet, there remains significant interest among practicing pathologists and their clinical colleagues to maintain expertise in the non-neoplastic arena, as evidenced by increasing volumes of non-neoplastic orthopedic diseases, often reflected in consult cases. Recent literature has renewed the discussion of arthroplasty, emphasized the clinical importance of pathologic examination, and provided updated diagnostic clarification for separating avascular necrosis from degenerative joint disease (DJD)/osteoarthritis (OA) with secondary osteonecrosis, acute infectious osteomyelitis from pseudoabscesses of DJD/OA, and revisited the diagnoses of subchondral insufficiency fracture and rapidly destructive arthropathy. Providing accurate neutrophil counts to help determine periprosthetic joint infection has rapidly become one of the most common sources of frozen section evaluation in the United States. Distinguishing periprosthetic joint infection from aseptic loosening has significant intraoperative implications. In addition to acute arthritis and mass effect, calcium pyrophosphate dihydrate (CPPD) deposition disease may lead to DJD/OA. However, most histologically confirmed examples of CPPD, involving the large extremity joints, are not identified preoperatively or radiologically, requiring pathologic evaluation to reliably establish the diagnosis. The incidence of CPPD deposits appears highest in the humeral head/shoulder, followed by the knees and hips/femoral head. Recent evidence has documented infrequent examples of combined gout and CPPD/pseudogout within the same tophi, associated with unique clinicopathologic features compared with those with gout alone. Carpal tunnel syndrome, trigger finger, and lumbar stenosis represent potential early red flags for the development of transthyretin (TR) cardiac amyloidosis. Although previously discarded at many institutions, excised tissue removed from such specimens, particularly tenosynovium from the carpal tunnel flexor retinaculum, are now routinely evaluated histologically with Congo red staining and, when positive, followed by mass spectrometry for confirmatory amyloid subtyping. With the use of a recently developed TR stabilizer, such as tafamidis, early histologic detection and treatment of TR cardiac amyloidosis has improved clinical outcomes. Herein is a summary of recent relevant developments in non-neoplastic orthopedic surgical pathology, updated diagnostic criteria and pitfalls, and the resulting clinical impact, where applicable.
Replacing Molecular Testing With Next-Generation Immunohistochemistry: I Can Diagnose That Soft Tissue Tumor With a Single Antibody!
Hornick JL
Mod Pathol · 2026 Jan · PMID 41086987 · Publisher ↗
Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Conventional immunohistochemistry uses antibodies directed against lineage-restricted antigens, in an attempt to identify a line of differ...
Immunohistochemistry plays a central role in the diagnosis of soft tissue tumors. Conventional immunohistochemistry uses antibodies directed against lineage-restricted antigens, in an attempt to identify a line of differentiation and narrow down the differential diagnosis. However, in most cases, such markers are inadequate to reach a specific diagnosis. Many soft tissue tumors harbor recurrent, often disease-defining molecular genetic alterations. Increasingly, fluorescence in situ hybridization analysis or next-generation sequencing is employed for identification of such alterations as a diagnostic adjunct. In recent years, immunohistochemistry has been used as a surrogate for such molecular genetic or cytogenetic analysis; this approach can identify the protein correlates of genetic alterations. Numerous next-generation antibodies directed against the protein products of a wide range of genetic alterations (such as gene fusions, amplifications, deletions, and point mutations) have entered our diagnostic armamentarium. In addition, gene expression profiling has uncovered diagnostically useful markers for immunohistochemistry. Finally, epigenetic alterations (eg, methylation) can also be assessed by immunohistochemistry. This review will provide examples of the application of contemporary molecular immunohistochemistry for soft tissue tumor diagnosis.
Giant Cell-Rich Tumors of Bone and Soft Tissue.
van der Linde RM, van IJzendoorn DGP, van de Rijn M … +1 more , Bovée JVMG
Mod Pathol · 2026 Jan · PMID 41082975 · Publisher ↗
Many benign and malignant bone and soft tissue tumors can contain giant cells in variable amounts. In some tumors, such as tenosynovial giant cell tumor and giant cell tumor of bone, these osteoclast-like giant cells are...
Many benign and malignant bone and soft tissue tumors can contain giant cells in variable amounts. In some tumors, such as tenosynovial giant cell tumor and giant cell tumor of bone, these osteoclast-like giant cells are so prominent and characteristic that their presence has defined the entity. Other examples of bone tumors in which the presence of osteoclast-like giant cells is characteristic include chondroblastoma, aneurysmal bone cyst, nonossifying fibroma, and central giant cell granuloma. These tumors have a distinct pathogenesis, although some parallels can be identified. The osteoclast-like giant cells within these tumors are not the neoplastic component but are nonneoplastic bystanders and part of the tumor microenvironment. Notably, the activation of the colony-stimulating factor 1 (CSF1)-CSF1 receptor (CSF1R) and/or the receptor activator of NFκB ligand-receptor activator of NFκB signaling pathways, best studied in tenosynovial giant cell tumor and giant cell tumor of bone, respectively, appears to be key in attracting macrophages and the formation of osteoclast-like giant cells within the tumor. Among soft tissue tumors, a plethora of tumors have been described to contain variable amounts of giant cells, and the underlying mechanisms are so far less well understood. One exception is the recently described keratin-positive giant cell-rich tumor of soft tissue, which also seems to rely on CSF1-CSF1R signaling to attract giant cells. The CSF1-CSF1R and receptor activator of NFκB ligand-receptor activator of NFκB pathways are suitable targets for nonsurgical interventions, and inhibitors of these pathways are already being used for some entities in clinical practice. These inhibitors inhibit tumor growth and may induce bone formation, although pathologists should be aware when evaluating posttreatment specimens that the neoplastic cells remain unaffected.
Comparative Analysis Reveals Recurrent Molecular Alterations in Low-Risk Human Papillomavirus 6 and Human Papillomavirus 11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva.
Sun Y, Smith C, Murray J … +9 more , Zhu J, Pallavajjala A, Liang S, Klausner M, Tsai YC, Hung CF, Wu TC, Zou YS, Xing D
Mod Pathol · 2025 Dec · PMID 41077352 · Full text
Although the association between human papillomavirus (HPV) 6 and HPV11 and squamous cell carcinomas (SCCs) has been well documented, the molecular alterations and mechanisms by which these low-risk HPVs contribute to ca...
Although the association between human papillomavirus (HPV) 6 and HPV11 and squamous cell carcinomas (SCCs) has been well documented, the molecular alterations and mechanisms by which these low-risk HPVs contribute to carcinogenesis remain largely unknown. In this study, we comparatively elucidated the molecular landscape of HPV6/11-associated condylomas (9 cases) and SCCs (8 cases) of the uterine cervix and vulva. Sixteen of 17 cases were successfully analyzed using deep next-generation sequencing. Recurrent molecular alterations in the SCCs included mutations in the TERT promoter (pTERT, 71%), NOTCH1 (57%), NFE2L2 (57%), NOTCH3 (29%), and CDKN2A (29%). Mutations in NOTCH1 and NFE2L2 tended to be mutually exclusive. Less common somatic mutations were each detected in the following genes: AR, ARID1A, ASXL1, BCORL1, DAZAP1, FNDC1, HRAS, KMT2B, NOTCH2, NRAS, PIK3R1, and TP53. Etiologically similar to the SCCs, the vast majority of vulvar and cervical condylomas (7/9, 78%) were infected with HPV6 rather than HPV11. Unlike the SCCs, condylomas rarely harbored recurrent pathogenic somatic mutations. NOTCH1 and NOTCH2 were the only mutant genes detected in both SCCs and condylomas in this series, suggesting a critical role for the NOTCH pathway in the initiation and maintenance of HPV6/11-related early squamous lesions. Although pathogenic mutations in NOTCH1, NOTCH2, ERBB3, ATRX, FGFR2, EPHA5, CARD11, STAG2, and TSC2 were detected in condylomas, none were recurrent, indicating diverse genetic alterations involved in the development of these lesions. Case 8 illustrated a stepwise progression from condyloma to invasive SCC, in which pathogenic mutations in pTERT and NOTCH1 were detected in the SCC (age 58) and the condyloma at age 55, but not in the condyloma at age 44. Our study presents the first report on the molecular landscape of HPV6/11-associated SCCs of the uterine cervix and vulva. We provide evidence that SCCs associated with low-risk HPV are distinct entities, differing from those related to high-risk HPV and more closely resembling HPV-independent neoplasms. Given that low-risk HPV-associated SCCs of the cervix and vulva exhibit unique morphological and molecular features, they should either be described separately within existing classification systems or classified as a distinct new entity.
Clinicopathologic and Molecular Genetic Features of Spindle Cell Rhabdomyosarcoma Harboring ZFP64::NCOA2/3 Fusions: A Series of 14 Cases.
Dehner CA, Ameline B, Amary F … +17 more , Gross JM, Zou Y, Michal M, Kinkor Z, Torres-Mora J, Malik F, Kao EY, Ricciotti RW, Din NU, John I, Dickson BC, Demicco EG, Agaimy A, Linos K, Hameed MR, Folpe AL, Baumhoer D
Mod Pathol · 2025 Dec · PMID 41075874 · Full text
Spindle cell rhabdomyosarcomas (SCRMS), recognized by the 2020 World Health Organization Classification of Tumors of Soft Tissue and Bone as a distinct entity, comprise a family of malignant skeletal muscle tumors sharin...
Spindle cell rhabdomyosarcomas (SCRMS), recognized by the 2020 World Health Organization Classification of Tumors of Soft Tissue and Bone as a distinct entity, comprise a family of malignant skeletal muscle tumors sharing spindle cell morphology. To date, members of this family include (1) MyoD1-mutated SCRMS/sclerosing rhabdomyosarcomas (RMS), (2) intraosseous SCRMS with FET::TFCP2 or MEIS1::NCOA2 fusions, and (3) infantile/congenital SCRMS harboring NCOA1/2 or VGLL3 rearrangements. A rare, emerging subtype of SCRMS has been reported to harbor recurrent ZFP64::NCOA3 fusions. We studied 14 cases of this rare SCRMS subtype. The tumors presented in 11 men and 3 women (median age, 39.5 years; range, 22-69 years) and involved the thigh (4), lower leg (2), gluteal soft tissues (2), abdominal wall (1), mediastinum (1), subperiosteal surface of third rib (1), glottis (1), prostate (1), and pelvis (1). Morphologically, 11 tumors showed uniform spindle cell morphology with a fascicular architecture, whereas the remaining 3 tumors demonstrated focal or predominant round cell morphology. Extensive chondro-osseous differentiation was seen in 2 cases. By immunohistochemistry, tumors were variably positive for both desmin and MyoD1 (6 tumors), desmin, MyoD1, and myogenin (1 tumor), desmin alone (3 tumors of which only 1 was also tested for MyoD1), or MyoD1 alone (3 tumors). Smooth muscle actin was noted in 6 of 10 tested cases, and 2 of 5 tested cases showed ALK expression. A ZFP64::NCOA3 fusion was detected in 8 tumors, and a ZFP64::NCOA2 fusion was detected in 6 tumors. Methylation studies showed all but 1 tested tumor to form a tight cluster, clearly separate from other RMS subtypes and non-RMS morphologic mimics. Clinical follow-up (10/14 cases; median, 35 months; range, 3-108 months) demonstrated local recurrence in 2 patients and distant metastases in 5 patients (median, 12 months; range, at presentation - 106 months). At the time of last follow-up, 5 patients were alive without evidence of disease, 3 patients were alive with disease, and 2 patients died of disease at 34 and 108 months. We conclude that SCRMS with ZFP64::NCOA2/3 fusions represents a distinct, clinically aggressive sarcoma characterized by fascicular and sometimes round cell morphology, occasional chondro-osseous differentiation, and variable skeletal muscle marker expression. Recognition of this emerging subtype of SCRMS may have prognostic and therapeutic implications.
Deep Learning-Based Segmentation of Lung Adenocarcinoma Whole-Slide Images for Objective Grading, Tumor Spread Through Air Spaces Identification, and Mutation Prediction.
Ho DJ, Chang JC, Aly RG … +5 more , Nguyen HCT, Adusumilli PS, Fuchs TJ, Travis WD, Vanderbilt CM
Mod Pathol · 2025 Dec · PMID 41075873 · Full text
Manual quantification of morphologic patterns in lung adenocarcinoma is subject to reproducibility issues due to interpathologist variability. In this study, we developed a deep learning-based multiclass segmentation mod...
Manual quantification of morphologic patterns in lung adenocarcinoma is subject to reproducibility issues due to interpathologist variability. In this study, we developed a deep learning-based multiclass segmentation model providing a modality for objective and quantitative grading of digitized lung adenocarcinoma images from resected specimens. Additionally, the model can detect tumor spread through air spaces and show enrichment of specific morphologic patterns in tumors with different genomic alterations. The study was based on 766 resected nonmucinous lung adenocarcinomas. Deep Multi-Magnification Network was trained to segment 14 tissue subtypes based on annotations of 108 internal whole-slide images at pixel level by thoracic pathologists (J.C.C. and W.D.T.). The trained model was validated on an external cohort of 130 cases for determining predominant patterns and on the remaining 528 internal cases for the 3 clinical tasks. The model graded nonmucinous lung adenocarcinomas based on the International Association for the Study of Lung Cancer Pathology Committee recommendation and successfully stratified patients into well, moderately, and poorly differentiated morphologies (P < 1 × 10). Pixels categorized as spread through air spaces significantly correlated with pathologists' interpretations. For molecular analysis, solid pattern was enriched with TP53 mutations and depleted of EGFR kinase domain mutations. Lepidic pattern was inversely associated with TP53 mutations. Acinar was enriched with EGFR mutations, whereas papillary was associated with RET fusions. Our study demonstrated that deep learning-based segmentation can accurately quantify histologic patterns in lung adenocarcinoma and identify additional prognostic features. By simultaneously providing an objective assessment of various tasks, our comprehensive methodology in lung adenocarcinoma paves way for deep learning-assisted pathologic diagnosis and treatment guidance.
Head-to-Head Comparison of 2 Artificial Intelligence Tools for Detecting Lymph Node Metastases in Whole-Slide Pathology Images Within and Beyond Their Intended Use.
Flach RN, Samuels M, Ter Hoeve ND … +9 more , Stathonikos N, Jonges TGN, Freund JE, Breimer GE, Blokx WAM, Schutgens F, Nguyen TQ, van Diest PJ, van Dooijeweert C
Mod Pathol · 2025 Dec · PMID 41072884 · Publisher ↗
The increasing diagnostic workload in pathology, driven by rising cancer incidences, highlights the need for scalable, cost effective solutions. Artificial intelligence (AI) has shown promise in supporting lymph node (LN...
The increasing diagnostic workload in pathology, driven by rising cancer incidences, highlights the need for scalable, cost effective solutions. Artificial intelligence (AI) has shown promise in supporting lymph node (LN) metastasis detection, a key prognostic factor in cancer staging. However, the current Conformité Européene In Vitro Diagnostics--certified AI tools are often limited to specific tumor types, reducing their cost efficiency and clinical use. This study evaluates the performance of 2 Conformité Européene In Vitro Diagnostics-certified AI tools-Visiopharm Metastasis Detection App (VMD) and DeepPath LYDIA (DPL)-for multipurpose LN metastasis detection across 6 tumor types, both within and beyond their intended use. We retrospectively analyzed whole-slide images from 455 patients with LN metastases from melanoma, colorectal, head and neck, lung, vulvar, and breast cancer. Both sentinel and nonsentinel LNs were included, with expert pathologists establishing the reference standard, according to clinical practice. Sensitivity was calculated per case and stratified based on metastasis size. False-positive alerts (FPAs) were assessed in 1012 tumor-negative slides. Both applications demonstrated excellent sensitivity for macrometastases across tumor types. DPL showed slightly higher sensitivity for micrometastases and isolated tumor cells compared with VMD, particularly in lung cancer and melanoma. FPA rates were substantial for both tools, with VMD generally producing more alerts, especially in lung and breast cancer. Our findings suggest that a single AI tool may be suitable for LN metastasis detection across multiple tumor types, even beyond its intended use. However, high FPA rates-particularly in lung cancer (inside intended use for DPL)-may limit practical use. Prospective studies are needed to confirm workflow efficiency gains and define optimal implementation strategies. These results support a broader, pragmatic approach to AI validation and regulatory approval, potentially improving the business case for AI adoption in pathology laboratories.
Genomic Profiling of Pediatric Mycosis Fungoides, Lymphomatoid Papulosis, and Primary Cutaneous Anaplastic Large Cell Lymphoma Identifies Recurrent Tyrosine Kinase Gene Fusions.
Fischer GM, Tsai HK, Huang J … +21 more , Mochel MC, Sadigh S, Pan Z, Montesion M, Williams EA, Sabbagh M, Chetta P, Lip V, Ferry JA, Reimann JDR, Duncan L, Chen S, Kupper T, Liang MG, Vrooman LM, Pollard J, Pouli D, Fleming MD, Schmidt B, Harris MH, Bledsoe JR
Mod Pathol · 2025 Dec · PMID 41072883 · Publisher ↗
Pediatric cutaneous T-cell lymphoproliferative disorders encompass a diagnostically complex set of rare diseases of undefined pathogenesis, including mycosis fungoides (MF), lymphomatoid papulosis (LyP), and primary cuta...
Pediatric cutaneous T-cell lymphoproliferative disorders encompass a diagnostically complex set of rare diseases of undefined pathogenesis, including mycosis fungoides (MF), lymphomatoid papulosis (LyP), and primary cutaneous anaplastic large cell lymphoma (pcALCL). In the pediatric population, these disorders are much less common than in adults, which has precluded systematic evaluation of their molecular pathogenesis. We report the clinicopathologic and molecular features of pediatric MF (n = 14, ages 5-17 years at diagnosis), LyP (n = 8, ages 4-17 years), and pcALCL (n = 2). Next-generation sequencing analysis (targeted 72-gene fusion panel, targeted 447-gene exome sequencing panel, and/or FoundationOneHeme) was performed. JAK2 fusions were detected in 64% (7/11) MF (PCM1::JAK2, ILF3::JAK2 [n = 2], ATXN2L::JAK2 [n = 2], and NUP214::JAK2 [n = 2]) by next-generation sequencing of available cases. TYK2 fusions were identified in 1 of 11 MF (novel LMNA::TYK2), 3 of 5 LyP (NPM1::TYK2 [n = 2], and novel RAN::TYK2), and 1 of 2 pcALCL (RAN::TYK2) cases tested. A novel NUP214::FRK fusion was observed in the other pcALCL. Fusions were in-frame and retained the kinase domain of the 3' partner in all cases. MF cases demonstrated clonal TCR gene rearrangements (12/12 tested). Treatment was heterogeneous, although it usually included narrowband ultraviolet B phototherapy for MF and topical steroids for MF and LyP. We demonstrate that pediatric MF, LyP, and pcALCL harbor frequent tyrosine kinase gene fusions with enrichment of JAK2 and TYK2 fusions, genomic alterations that are diagnostically useful and may be amenable to targeted therapy.
Corrigendum to "Magnetic Resonance Imaging (MRI)-Adapted Prostate Cancer Risk Tool Incorporating Cribriform and Intraductal Carcinoma" (Modern Pathology 2025 Dec;38(12):100852).
Jennifer Nguyen NN, Liu K, Lajkosz K … +9 more , Bernardino R, Yin LB, Hollemans E, Kroon LJ, Fleshner N, van Leenders GJLH, Iczkowski KA, van der Kwast TH, Downes MR
Mod Pathol · 2025 Dec · PMID 41061340 · Publisher ↗
Abstract loading — click title to view on PubMed.
Corrigendum to "Spatial Evaluation and Prognostic Significance of V-Domain Immunoglobulin Suppressor of T-Cell Activation (VISTA) in Human Resectable Cervical Carcinoma: Implications for Immune Activation and Suppression" [Modern Pathology 2025;38(12):100851].
Xie Q, Li J, Li J … +8 more , Liu C, Li Y, Zeng H, Yu J, Wu Y, Chen K, Zhang Z, Wang B
Mod Pathol · 2025 Dec · PMID 41061339 · Publisher ↗
Abstract loading — click title to view on PubMed.
A Rational Approach to the Diagnosis of Liver Metastases.
Hu S, Allende DS
Mod Pathol · 2025 Dec · PMID 41046012 · Publisher ↗
The diagnosis of liver metastases encompasses a broad spectrum of entities and relies on clinicopathological correlation, with some cases being diagnosable using hematoxylin and eosin staining alone. For more challenging...
The diagnosis of liver metastases encompasses a broad spectrum of entities and relies on clinicopathological correlation, with some cases being diagnosable using hematoxylin and eosin staining alone. For more challenging cases, ancillary testing is often required, with a focus on maximizing diagnostic yield while preserving tissue. This review draws on years of experience at a high-volume, tertiary referral center and incorporates an in-depth analysis of the existing literature in the field. When evaluating a liver lesion, the first step is to determine whether it represents a primary hepatic tumor or a metastasis. This review discusses a practical panel of immunohistochemical stains valuable in making this distinction. Next, it outlines a morphologic pattern-based approach to metastatic liver tumors, categorized by epithelioid, spindle, undifferentiated, and small round blue cell morphology. For each category, readers will find a proposed list of differentials based on the morphologic pattern, a suggested screening immunohistochemical panel, a focused discussion of potential pitfalls and practical tips for ancillary testing ("important aspects of ancillary testing"), and additional insights on specific entities within each group ("special diagnostic considerations"). This review provides a comprehensive overview of the diagnosis of liver metastases, along with a current guide to immunohistochemical and molecular testing for the classification of these tumors. It underscores the importance of careful consideration and prioritizing site-agnostic biomarkers and tumor lineage classification (eg, carcinoma, sarcoma, lymphoma, or melanoma) when choosing ancillary stains in challenging cases with limited material.
Predicting the Probability of Residual Axillary Nodal Metastases in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy.
Khoury T, Zhan H, Huang X … +8 more , Ghasemi F, Rajack F, Yuan G, Yu H, Theriot J, Bragiel R, Okamoto K, Ali M
Mod Pathol · 2025 Dec · PMID 41043643 · Full text
In patients with breast cancer treated with neoadjuvant chemotherapy (NACT), a positive sentinel lymph node (SLN) usually requires completion axillary lymph node dissection (ALND). To enable de-escalation of this traumat...
In patients with breast cancer treated with neoadjuvant chemotherapy (NACT), a positive sentinel lymph node (SLN) usually requires completion axillary lymph node dissection (ALND). To enable de-escalation of this traumatic surgery, we aimed to develop a model to accurately estimate the likelihood of axillary disease after a positive SLN biopsy in the NACT setting. We retrospectively analyzed clinicopathological data from 237 patients composed of a training set of 150 patients from a single institution and a validation set of 87 patients from 2 other institutions. Variables that were collected included the histologic type, lymphovascular invasion, the number of lymph nodes (LNs) (SLN and non-SLN), positive and negative, with and without treatment effect, extranodal extension, and the calculated residual cancer burden of the largest SLN metastasis. Residual axillary disease was defined as ≥1 positive LNs in the completion ALND specimen. Univariable and multivariable statistical analyses were performed. Then, a formula for the risk of predicted probability of residual axillary disease was created using a stepwise feature selection based on the Akaike Information Criterion to select variables in the model. Residual axillary disease was identified in 120 out of 237 (50.6%) cases (73 [48.7%] in the training set and 47 [54%] in the validation set). Independent predictors of residual axillary disease in the multivariable model included the greatest dimension of the largest SLN metastasis, lymphovascular invasion, greater number of positive LNs with no treatment effect, greater number of positive LNs with treatment effect, greater number of negative LNs with treatment effect, and fewer number of negative LNs. These variables along with residual cancer burden of the largest SLN metastasis and histologic type were incorporated into the final model by stepwise feature selection. The predictive formula achieved an area under the curve of 77.6% for the training set and 69.7% for the validation set. A predicted probability value of ≤20% yielded a negative predictive value of 86.5% in the training set and 64.7% in the validation set. This corresponds to 37 (25.3%) patients who could be spared ALND in the training set and 17 (19.5%) in the validation set. Using the formula, a subset of patients treated with NACT could be spared unnecessary ALND.
Artificial Intelligence (AI)-Driven Screening of Equivocal Prostate Immunohistochemistry (IHC) Cases: Development and Validation of a Screening and Cancer Detection Framework.
Nateghi R, Zhou R, Saft M … +18 more , Schnauss M, Neill C, Alam R, Handa N, Huang M, Li EV, Goldstein JA, Patel HD, Schaeffer EM, Nadim M, Pourakpour F, Isaila B, Felicelli C, Mehta V, Nezami BG, Ross AE, Yang XJ, Cooper LAD
Mod Pathol · 2025 Dec · PMID 41043642 · Full text
Artificial intelligence (AI) has been proposed as a solution to meet increasing demand for the diagnostic services of pathologists (B.I., C.F., V.M., B.G.N., X.J.Y.). Prostate biopsies are a significant source of this de...
Artificial intelligence (AI) has been proposed as a solution to meet increasing demand for the diagnostic services of pathologists (B.I., C.F., V.M., B.G.N., X.J.Y.). Prostate biopsies are a significant source of this demand, and a substantial fraction of these biopsies require immunohistochemistry (IHC) staining, which adds work, time, and cost to the diagnostic process. Equivocal cases, which often prompt the use of IHC, not only present the greatest challenge to AI cancer detection tools but also represent the area where properly trained systems could offer the most clinical value by reducing the need for ancillary testing for cancer confirmation. From August 2021 to April 2023, we scanned 25,570 slides from 1641 patients. We investigated the performance of institutionally developed models for prostate cancer detection using digital pathology images, with an aim for reducing work, turnaround time, and costs related to the ordering of IHC equivocal cases. We advanced complementary sensitive and specific models to screen these challenging cases, aiming to identify slides that could be confidently diagnosed without any ancillary IHC tests. Additionally, we compared the performance of a prostate-specific model to a general-purpose foundation model for screening and cancer detection. Our screening models correctly classified 55% of challenging equivocal blocks where IHC was ordered with a 1.4% error rate. We found that the foundation model achieved higher screening rates (ie, percentage of cases where IHC could be avoided), but this came at the cost of uniformly higher error rates and significantly greater computational demands. When trained as a standalone prostate cancer detection system, our model demonstrated high concordance with pathologist ground truth, achieving an area under the curve of 98.5%, sensitivity of 95.0%, and specificity of 97.8%. Computational models can aid in the diagnosis of prostate cancer and can effectively screen challenging prostate biopsy cases, reducing unnecessary IHC utilization and helping to optimize pathology workflows. Plain language summary Traditional pathologic diagnosis of prostate cancer can be labor intensive. Equivocal cases in particular often require special testing (immunohistochemistry [IHC]) to establish a diagnosis, which introduces further delay and cost. This study develops an artificial intelligence system specifically designed to screen equivocal cases and reduce the need for IHC. Our model serves as a second-read tool to help optimize pathology workflow and reduce turnaround time and costs by flagging cases where IHC can be safely avoided.
GLUT1 Expression Patterns in Verruciform Acanthotic Vulvar Squamous Intraepithelial Neoplasia, HPV-Independent p53 Wild-Type Squamous Cell Carcinoma and Benign Vulvar Lesions.
Zhang G, Soslow RA, Yang B
Mod Pathol · 2025 Dec · PMID 41033580 · Publisher ↗
Verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) is a rare type of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (SCC) precursor lacking aberrant p53 expression. Our recent study de...
Verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) is a rare type of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (SCC) precursor lacking aberrant p53 expression. Our recent study demonstrated GLUT1 overexpression in vulvar SCC and identified 2 distinct patterns in HPV-associated high-grade squamous intraepithelial lesions and HPV-independent differentiated vulvar intraepithelial neoplasia. Herein, we expand on our study by assessing GLUT1 expression in 24 cases of vaVIN and 8 cases of associated invasive SCC, compared with 48 cases of benign vulvar squamous lesions, including 40 cases of non-HPV benign vulvar lesions and 8 cases of condyloma associated with low-risk HPV infection. GLUT1 immunohistochemistry (IHC) demonstrated consistent diffuse GLUT1 immunostaining in all vaVIN cases. The GLUT1 immunostaining pattern in vaVIN is characterized by strong membranous staining in the basal layer with suprabasal extension to the full thickness of intermediate layers. In vulvar SCC associated with vaVIN, GLUT1 expression was prominent at the periphery of tumor nests without expression in the central portion. GLUT1 IHC revealed weak peri-papillae or intensified peri-papillae patterns in non-neoplastic vulvar lesions and HPV-related patterns in condyloma. The GLUT1 immunostaining patterns in vaVIN and associated SCC are different from benign mimickers, but similar to those of differentiated vulvar intraepithelial neoplasia and associated SCC, despite distinct molecular alterations and pathways. The latter suggests that upregulation of GLUT1 is likely a common metabolic pathway shared by 2 types of HPV-independent VINs, regardless of p53 status. GLUT1 IHC is highly sensitive in detecting vaVIN. However, the specificity rests on recognizing GLUT1-staining patterns in benign mimickers of vaVIN. Along with HPV chromogenic in situ hybridization and other well-characterized biomarkers, GLUT1 immunochemistry can be a helpful adjunct in assisting the diagnosis of vaVIN.
Human Epidermal Growth Factor Receptor 2 (HER2)-Ultralow Breast Cancer: Incidence, Clinicopathologic Features, and Need for Refined Scoring System.
Morrar D, Brogi E, Schwartz CJ … +3 more , Pareja F, Wen HY, Ross DS
Mod Pathol · 2025 Dec · PMID 41033579 · Full text
Patients with metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC), defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization negative, have demonstrated clinical benefit from...
Patients with metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC), defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization negative, have demonstrated clinical benefit from antibody-drug conjugates, such as trastuzumab deruxtecan. The DESTINY-Breast06 trial further demonstrated that patients with hormone receptor-positive, HER2-ultralow (UL) metastatic BC also benefit from HER2-targeted therapies. This study aimed to evaluate the incidence, staining characteristics, and clinicopathologic features of HER2-UL BC. We retrospectively analyzed scanned HER2 IHC slides (PATHWAY anti-HER2/neu 4B5) from 400 primary BC cases diagnosed between January and March 2024. Two breast pathologists reevaluated and recategorized HER2 IHC results into HER2-positive, HER2-low, HER2-UL, and HER2-null (N). HER2-UL was defined as incomplete or weak membranous staining in ≤10% of tumor cells, whereas HER2-N showed complete absence of membranous staining. Staining was analyzed by distribution, location, and quality. Clinicopathologic comparisons were performed across HER2-negative groups. Original HER2 classification based on the 2023 American Society of Clinical Oncology and College of American Pathologists guidelines included HER2 IHC 0 (146, 37%), HER2 IHC 1+ (188, 47%), HER2 IHC 2+/fluorescence in situ hybridization negative (33, 8%), and HER2-positive (HER2 IHC 2+/fluorescence in situ hybridization positive or 3+) (33, 8%). Upon rereview, with HER2-low, HER2-UL, and HER2-N incorporated into the classification framework, 63 cases (16%) were HER2-N, 118 (29%) HER2-UL, 186 (47%) HER2-low, and 33 (8%) HER2-positive. In HER2-UL cases, median membranous staining was 3% (range, 1%-9%). Nonspecific staining patterns, such as granular cytoplasmic staining, cytoplasmic blush, edge staining, and dot-like peritumoral staining, were frequently observed in recategorized cases. No significant clinicopathologic differences were found among HER2-N, HER2-UL, and HER2-low groups, except for higher invasive lobular carcinoma frequency in HER2-N (P = .034) and older age in HER2-UL patients. Notably, 55% (80/146) of initial HER2 IHC 0 cases were categorized as HER2-UL. As HER2-targeted therapies expand to HER2-UL tumors, accurate classification is critical. Implementation of a refined scoring system could improve diagnostic accuracy and therapeutic targeting.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe